The treatment of cognitive impairment in schizophrenia
Donald C. Goff, Michele Hill, Deanna Barch
PII:
DOI:
Reference:

S0091-3057(10)00347-3
doi: 10.1016/j.pbb.2010.11.009
PBB 71044

To appear in:

Pharmacology

Received date:
Revised date:
Accepted date:

9 September 2010
5 November 2010
12 November 2010

Please cite this article as: Go Donald C., Hill Michele, Barch Deanna, The
treatment of cognitive impairment in schizophrenia, Pharmacology (2010),
doi:
10.1016/j.pbb.2010.11.009

This is a PDF le of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its nal form. Please note that during the production process
errors may be discovered which could aect the content, and all legal disclaimers that
apply to the journal pertain.

ACCEPTED MANUSCRIPT

RI
P

Words: 5468
Tables :0
Figures: 0

MA

NU

SC

The treatment of cognitive impairment in schizophrenia

Donald C. Goff1
Michele Hill1

PT

ED

Deanna Barch2

The Schizophrenia Program, Massachusetts General Hospital and Harvard Medical School

Washington University, Departments of Psychology, Psychiatry and Radiology

AC
CE

Corresponding author:
Donald Goff, MD
Freedom Trail Clinic
25 Staniford St.
Boston, MA 02114
617 912 7862
Fax: 617 723 3919
goff@psych.mgh.harvard.edu
Supported by MH002025 (DG)

ACCEPTED MANUSCRIPT

1. Introduction:

RI
P

1.1 Cognitive Deficits in Schizophrenia:

The field of psychopathology research has increasingly come to recognize the importance of

SC

cognitive deficits in understanding etiology, course and outcome in schizophrenia (Green et al.,
2000; Keefe, 2008), one of the most debilitating of psychiatric disorders. The range of cognitive

NU

impairments in individuals with schizophrenia is broad, with the more robust and replicable
deficits typically found in the domains of processing speed, episodic memory, working memory,

MA

and executive function. Impairments in these domains are associated with alterations in the
neural systems known to support these cognitive functions, including impairments in the

ED

function of the medial temporal lobes (Heckers, 2001; Reichenberg and Harvey, 2007), the
prefrontal cortex (Minzenberg et al., 2009), and a range of neurotransmitter systems known to be

PT

important for intact cognitive function. These cognitive impairments are typically present prior

AC
CE

to the onset of the illness (Cornblatt et al., 1999; Niendam et al., 2003), and there is even some
data to suggest that the degree of impairment in certain aspects of cognition predicts the
subsequent onset of schizophrenia (Cornblatt et al., 1999; Sorensen et al., 2006). Importantly,
individuals who share unexpressed genetic components of vulnerability to schizophrenia also
experience impairments in cognitive function, including first degree relatives (Delawalla et al.,
2006; Snitz et al., 2006) and individuals with schizotypal personality disorder (Barch et al., 2004;
Dickey et al., 2005; Voglmaier et al., 2000). In addition, some evidence suggests that the
stronger the genetic risk, the greater the impairment in cognitive function in first-degree relatives
(Glahn et al., 2003; Tuulio-Henriksson et al., 2003). These cognitive deficits persist throughout
the course of the illness in individuals with schizophrenia (Heaton et al., 2001; Irani et al.), and
may be important in constraining functional outcome and quality of life (Gold et al., 2002; Green

ACCEPTED MANUSCRIPT

et al., 2004). Thus, it is a high priority to identify the biological underpinnings of cognitive

RI
P

deficits in schizophrenia and to develop effective treatments.

SC

1.2 Trial Design for Agents to Treat Cognitive Deficits in Schizophrenia:

In 2003, experts from academia, industry, and the FDA were brought together by the NIMH-

NU

funded Measurement and Treatment Research to Improve Cognition in Schizophrenia

(MATRICS) project to develop guidelines for clinical trials of cognitive enhancing drugs for

MA

schizophrenia (Buchanan et al., 2005). One of several accomplishments by this group was the
creation of the MATRICS consensus cognitive battery (MCCB), which tests seven domains of

ED

cognition intended to represent functionally-significant areas of impairment in schizophrenia that

may be amenable to pharmacologic treatment (Nuechterlein and Green, 2006); the MCCB has

PT

become the standard assessment tool for clinical trials. Although cognitive tests were selected to

AC
CE

minimize practice effects, experience with the MCCB indicates that small practice effects may
complicate the interpretation of results and so a placebo control is necessary in clinical trials
(Buchanan et al., 2010b). However, this issue of practice effects is not unique to the MCCB and
will be an issue with almost any cognitive battery. In addition, because no agent has established
efficacy for cognition in schizophrenia, an active control condition is not available to provide a
measure of assay sensitivity (i.e., the ability of the trial to differentiate active drug from placebo).
As a result, negative trials of cognitive enhancing agents cant be differentiated reliably from
failed trials, in which an effective agent would also fail to separate from placebo.

Several other issues were raised during the MATRICS discussion of clinical trial design,
including a concern on the part of the Food and Drug Administration (FDA) about

ACCEPTED MANUSCRIPT

pseudospecificity, or the possibility that cognitive function might be improved indirectly by a

drug that primarily improves psychosis, agitation, apathy, Parkinsonism or mood. Precautions to

RI
P

avoid secondary causes of cognitive impairment in participants were recommended, such as

restricting study samples to patients who are stable, without significant psychosis, depression,

SC

Parkinsonism, negative symptoms or use of drugs that impair cognition, such as anticholinergics
and benzodiazepines. It remains unclear whether common neurobiologic mechanisms may

NU

underlie both cognitive deficits and negative symptoms of schizophrenia, and so the wisdom of

MA

excluding patients with negative symptoms is debated (Buchanan et al., 2010b). The consensus
view of experts at the MATRICS meeting was that most patients with schizophrenia have
experienced some decrement in cognitive functioning associated with the illness; hence the only

ED

restrictions regarding cognitive functioning in subject selection are that participants are not at the

PT

ceiling level for a test nor too impaired to provide valid results. Because the second
generation antipsychotics bind to a wide range of receptors, potential pharmacodynamic

AC
CE

interactions may complicate add-on trials of cognitive enhancing agents. Drugs known to
possess the potential for pharmacodynamic or pharmacokinetic interactions with the
experimental agent may be best excluded at early stages of clinical development prior to
embarking on an all-comers approach to enrollment.

A common problem with trials of cognitive enhancing agents has been the analysis in small
subject samples of more than one cognitive test score without correction for multiple
comparisons, thus increasing the likelihood of false positive results. As such, it is recommended
that investigators use a single composite cognitive score or, if a priori evidence supports it, a
single domain score, as the primary outcome measure. If the composite cognitive score

ACCEPTED MANUSCRIPT

significantly improves with treatment compared to placebo, additional sub-analyses of cognitive

domains can be performed as exploratory analyses. The FDA also requested a co-primary

RI
P

outcome measure of function, such as the UCSD Performance Based Skills Assessment (UPSA)
(Patterson et al., 2001). According to the FDA position expressed at the MATRICS meetings,

SC

both co-primary outcome measures (cognitive score and functional outcome) must be
significantly improved compared to placebo in order for the trial to be considered a positive

MA

NU

demonstration of drug efficacy.

2. Pharmacologic Targets for Cognitive Enhancement in Schizophrenia:

ED

Many different drug targets and strategies for drug development have been employed for

PT

enhancement of cognition in schizophrenia; the relative lack of success to-date indicates the
difficulty that this therapeutic area poses. Receptor targets have been identified on the basis of

AC
CE

pharmacologic challenges that mimic schizophrenia (e.g., dopamine agonists and NMDA
receptor antagonists), receptor abnormalities found on postmortem analysis of schizophrenia
brain, and genetic linkage studies. Other approaches have emphasized the use of drugs that
enhance learning or memory in animal models, or that are effective in other disorders of
cognitive dysfunction, without a specific link to schizophrenia. More recently, investigators
have focused on putative neuroprotective agents and drugs that may enhance neuroplasticity or
neurogenesis.

It is possible that heterogeneity of mechanisms responsible for cognitive deficits in schizophrenia

may in part be responsible for the lack of success of any single approach and that matching of

ACCEPTED MANUSCRIPT

treatments to appropriate subgroups of patients may be necessary to establish efficacy.

Subgroups could be broadly based on theoretical etiologies of cognitive deficit

RI
P

(neurodevelopmental, biochemical or neurodegenerative), or on genetic markers, and could

treatment could entail strategies of prevention for neurodevelopmental processes, genetically-

SC

defined pharmacological augmentation or supplementation for biochemical deficits, and

neuroprotective approaches for neurodegenerative processes (Goff, 2005). Recent promising

NU

results with cognitive remediation have raised the possibility that promotion of neuroplasticity

MA

could be an effective approach for a wider range of etiologies.

2.1 Dopamine:

ED

Dopamine neurotransmission has long been central to models of schizophrenia and its treatment

PT

(Davis et al., 1991). Dopamine agonists produce psychosis indistinguishable from schizophrenia
in healthy individuals, although cognitive impairment is not prominent. The revised model of

AC
CE

dopamine dysregulation posits excessive activity in mesolimbic pathways producing psychosis

and diminished activity in prefrontal cortex producing cognitive deficits and negative symptoms
(Davis et al., 1991). Dopamine release in the striatum in response to amphetamine is increased
in medication-naive schizophrenia subjects compared to healthy controls and correlates with
psychotic symptoms in chronic patients (Laruelle and Abi-Dargham, 1999). Cognitive deficits
of schizophrenia, including attention and memory, are predicted by COMT genotype, believed to
reflect dopamine metabolism in forebrain (Egan et al., 2001),. All currently-approved
antipsychotic agents block D2 receptors and may improve cognitive function, although whether
this represents a direct effect rather than a secondary effect resulting from improvement of
psychotic disorganization, is difficult to establish. Of note, chronic antipsychotic treatment may

ACCEPTED MANUSCRIPT

also adversely affect cognition. Castner and colleagues (Castner et al., 2000) demonstrated

progressive cognitive impairment in monkeys exposed to haloperidol over a six month period; in

RI
P

addition, histopathological evidence of neuropathology characteristic of schizophrenia was found

after healthy monkeys were exposed to haloperidol or olanzapine for approximately two years

SC

(Dorph-Petersen et al., 2005; Konopaske et al., 2007). However, it is also possible that
antipsychotics have a different effect in populations with an underlying impairment, and thus

NU

findings of haloperidol induced cognitive impairment in healthy animals may not generalize to

MA

schizophrenia. Based on early uncontrolled trials, an expectation was widely held that cognition
would improve with second generation antipsychotics compared to first generation. However,
the CATIE trial failed to find any advantage of second generation agents compared to the

ED

representative first generation agent, perphenazine (Keefe et al., 2007). Nonetheless, uncertainty

PT

regarding chronic antipsychotic effects upon cognition complicates interpretation of add-on

AC
CE

strategies for cognitive enhancement.

2.1.1 Psychostimulants

Psychostimulants act by increasing release of dopamine and norepinephrine and are a wellestablished treatment for attentional disorders. Mattay and colleagues (Mattay et al., 2000)
found that D-amphetamine improved working memory in healthy subjects who performed poorly
at baseline, whereas working memory worsened in subjects with superior working memory
performance. In a subsequent study, COMT genotype predicted enhanced prefrontal activation
in response to D-amphetamine as assessed by fMRI during a working memory task in healthy
subjects (Mattay et al., 2003). Similarly, COMT genotype predicted improvement of executive

ACCEPTED MANUSCRIPT

functioning and verbal episodic memory in healthy subjects in response to the COMT inhibitor,

RI
P

tolcapone (Apud et al., 2007).

Due to concerns about exacerbating psychosis, psychostimulants have not been widely used in

SC

schizophrenia, although controlled studies have provided some evidence of cognitive

improvement without symptomatic worsening when D-amphetamine is added to antipsychotics

NU

in single-dose trials. In schizophrenia patients treated with haloperidol, D-amphetamine was

MA

found to enhance prefrontal cortical activation during performance of the Wisconsin Word Sort
Test and to improve processing speed, whereas performance on memory and attentional tasks did
not improve significantly (Daniel et al., 1991; Goldberg et al., 1991). Barch and Carter (Barch

ED

and Carter, 2005) found that, compared to placebo, D-amphetamine improved reaction times on

PT

spatial memory and Stroop tests, working memory accuracy, and language production when
added to first generation antipsychotics; healthy subjects displayed a similar pattern of cognitive

AC
CE

improvement except working memory accuracy did not change. Pietrzak and colleagues
(Pietrzak et al., 2010) reported improvement in executive function, attention, and speed of
processing with D-amphetamine compared to placebo in chronic schizophrenia patients.

2.1.2 D1 Agonists:
D1 activation in prefrontal cortex has been linked to working memory in an inverted U-shaped
relationship, such that both low and excessively high levels of D1 activation are associated with
impaired memory (Goldberg et al., 1991). D1 sensitivity has been shown in monkeys to decrease
with age and with chronic antipsychotic administration in concert with diminished working
memory (Goldman-Rakic et al., 2004). Intermittent treatment with a D1 agonist was shown to

ACCEPTED MANUSCRIPT

sensitize D1 receptors and improve memory in both aged (Castner and Goldman-Rakic, 2004)

and antipsychotic-treated (Castner et al., 2000) monkeys. Clinical trials of D1 agonists in

RI
P

schizophrenia have been delayed due to poor tolerability related to orthostatic hypotension and
nausea. However, a single low dose of the short-acting, selective D1 agonist, dihydrexidine,

SC

recently was adequately tolerated in schizophrenia subjects and acutely increased both prefrontal
and non-prefrontal cortical perfusion (Mu et al., 2007). Cognitive testing performed five hours

NU

after subcutaneous injection of dihydrexidine showed no effect, but due to its 30 minute half-life,

MA

blood levels of dihydrexidine were essentially undetectable at the time of cognitive testing
(George et al., 2007).

ED

2.1.3 Conclusion:

PT

Consistent with effects in healthy subjects and individuals with attention deficit disorder,
amphetamine may produce some improvement of concentration, memory and processing speed

AC
CE

and co-administration with antipsychotics appears to protect against psychotic exacerbation by

the psychostimulant, although long-term effects with repeated dosing remain uncertain. Agents
that inhibit COMT are promising, particularly when subjects are selected by COMT genotype,
although concerns about hepatotoxicity make tolcapone, the only currently-approved COMT
inhibitor, problematic. If tolerability issues can be surmounted, D1 selective agonists appear quite
promising, perhaps following an intermittent schedule of dosing as developed by Castner and
colleagues (Castner and Goldman-Rakic, 2004) to optimally sensitize prefrontal D1 receptors.

2.2 Glutamate:

ACCEPTED MANUSCRIPT

Over the past decade, models of glutamatergic dysregulation have gained prominence for drug

development in schizophrenia (Goff and Coyle, 2001; Javitt, 2004). This approach followed

RI
P

from observations that the NMDA channel blockers, ketamine and phencyclidine, produce
psychotic and negative symptoms and cognitive deficits suggestive of schizophrenia in healthy

SC

subjects, and symptom exacerbation in stable schizophrenia patients. Chronic phencyclidine

abuse is associated with a persistent psychotic syndrome and cognitive deficits often

NU

indistinguishable from schizophrenia (Javitt and Zukin, 1991; Jentsch and Roth, 1999). This

MA

model compliments the dopamine model, since ketamine replicates in healthy subjects the excess
striatal dopamine release in response to amphetamine observed in schizophrenia (Kegeles et al.,
2000). The glutamate dysregulation model increasingly has focused on NMDA receptors located

ED

on GABAergic inhibitory interneurons (Lisman et al., 2008); disruption of inhibitory input is

PT

expected to produce excessive glutamate release, aberrant spread of excitatory transmission, and
loss of neuronal network synchronization necessary for working memory and other cognitive

AC
CE

functions (e.g. gamma oscillations). The administration of ketamine in rodents is now widely
used to screen for cognitive enhancing agents; while this approach has identified some agents
with possible benefit for negative symptoms, translation into clinically-effective agents for
cognition has largely been unsuccessful, raising questions about the predictive validity of this
model.

2.2.1 Glycine site agonists:

Because excessive activation of the NMDA receptor can produce neurotoxicity, early treatment
studies focused on the glycine modulatory site of the NMDA receptor. The glycine-site agonists,
glycine, D-serine, and D-alanine, produced improvement in negative symptoms in small trials

ACCEPTED MANUSCRIPT

and some improvement in measures of cognition, although formal cognitive testing was not

performed (Tuominen et al., 2005). D-cycloserine, which, depending on the subunit composition

RI
P

of NMDA receptors, is either a partial or full-agonist (Dravid et al., 2010), demonstrated

inconsistent improvement of negative symptoms and no improvement in two studies that utilized

SC

formal cognitive testing (Goff et al., 1999; Goff et al., 2005). In the large CONSIST study,
neither glycine nor D-cycloserine improved negative symptoms or cognition (Buchanan et al.,

MA

NU

2007).

Recently, Kantrowitz and colleagues (Kantrowitz et al., 2010) conducted 4-week open-label addon trials of D-serine 30 mg/d, 60 mg/d and 120 mg/d to establish safety and tolerability with

ED

escalating doses. Significant cognitive improvements of large effect size were noted at high

PT

doses (60 mg/d and 120 mg/d) but not at the low dose (30 mg/d); cognitive improvement
correlated with plasma D-serine levels and was associated with reductions in psychosis and

AC
CE

negative symptoms.

It has been well-established that single dose administration of D-cycloserine improves

consolidation of memory in animal models, and that once-weekly dosing improves response to
cognitive behavioral therapy in patients with anxiety disorders (Davis et al., 2006). However,
repeated daily dosing results in rapid tolerance for cognitive effects (best studied with fear
extinction) (Parnas et al., 2005), believed to reflect trafficking of NMDA receptors from the cell
membrane to the intracellular compartment (Nong et al., 2003). In a recent study, a single dose
of D-cycloserine improved memory consolidation (7-day delayed recall) on the Logical Memory
Test of the revised Wechsler Memory Scale and once-weekly dosing produced persistent

ACCEPTED MANUSCRIPT

improvement of negative symptoms in patients with schizophrenia (Goff et al., 2008a). Another

strategy to avoid tachyphylaxis with NMDA receptor activation is to target intracellular

RI
P

pathways downstream of NMDA receptors. In one unsuccessful example, the PDE 5 inhibitor,
sildenafil, did not improve cognition in a placebo-controlled single-dose crossover trial (Goff et

SC

al., 2009). Several other agents targeting intracellular second messengers, including inhibitors of
PDE 2, 4, 9 and 10, are in development as potential cognitive enhancers (Reneerkens et al.,

MA

NU

2009).

2.2.2 Glycine reuptake inhibitors and AMPA modulators:

Other approaches to enhance NMDA channel opening via the glycine recognition site include

ED

glycine reuptake blockers (Javitt, 2009) and the reduction in levels of the endogenous glycine

PT

site antagonist, kynurenic acid, by enzymatic inhibitors (Potter et al., 2010). Several studies with
the weak endogenous glycine reuptake inhibitor, sarcosine, demonstrated efficacy for negative

AC
CE

symptoms, but formal cognitive testing results have not been reported (Lane et al., 2009; Tsai et
al., 2004). Selective glycine reuptake inhibitors (GlyT1) are currently under development with
preliminary results suggestive of benefit for negative symptoms but not cognition. Positive
modulators of the glutamatergic AMPA receptor enhance NMDA channel opening and long term
potentiation (LTP) by initiating rapid cellular depolarization (Black, 2005). In animal models,
single and intermittent dosing with AMPA positive modulators, produced improvement in
learning and memory (Hampson et al., 1998; Staubli et al., 1994), as did a pilot trial of daily
dosing with the short-acting, relatively low-potency ampakine, CX516, in clozapine-treated
schizophrenia patients (Goff et al., 2001). However, a large four-week add-on trial with daily
dosing of CX516 failed to demonstrate cognitive or symptomatic benefit (Goff et al., 2008b).

ACCEPTED MANUSCRIPT

2.2.3 Lamotrigine and metabotropic glutamate receptor agonists:

RI
P

Therapeutic strategies have also focused on the reduction of excessive postsynaptic glutamate
release hypothesized to result from dysfunction of NMDA receptors on inhibitory interneurons.

SC

Lamotrigine, which reduces glutamate release, attenuated ketamine effects on cognition in

healthy subjects (Anand et al., 2000) and one of two large trials found significant improvement

NU

on the composite cognitive score with lamotrigine up to 400 mg daily compared to placebo (Goff

MA

et al., 2007). Similarly, the metabotropic mGlu2/3 agonist, LY354754, which also reduces
glutamate release (Moghaddam and Adams, 1998), attenuated working memory deficits
produced by ketamine in healthy subjects (Krystal et al., 2005). However, studies of mGluR2/3

ED

agonists have not produced consistent evidence of cognitive benefit in animal models

PT

(Schlumberger et al., 2009). The mGluR2/3 agonist prodrug, LY2140023, administered as

monotherapy, significantly improved positive and negative symptoms in schizophrenia patients

AC
CE

in one of two trials, but cognitive effects were not reported (Patil et al., 2007). A more recent
class of glutamatergic agents, mGluR5 allosteric modulators, have demonstrated dose-dependent
improvement of recognition memory in rats (Uslaner et al., 2009) but results of human trials are
not yet available.

2.2.4 Conclusion:
Glutamatergic dysregulation is a compelling model for schizophrenia, with converging evidence
from genetics, postmortem histopathology and pharmacologic provocation of symptoms.
However, clinical trials of agents representing a wide range of glutamate-related strategies have
provided very little evidence of cognitive enhancement. The recent findings with open-label

ACCEPTED MANUSCRIPT

high-dose D-serine are quite promising and require replication in controlled trials. The best

evidence to-date comes from a multicenter trial of lamotrigine, although a second trial failed to

RI
P

replicate this finding. Single-dose administration of D-cycloserine has strong support from the
animal literature and has shown promise in one small study, whereas strategies that produce

SC

persistent elevation of glycine site occupancy have improved negative symptoms response
without strong evidence of cognitive enhancement. Several additional approaches await clinical

MA

NU

trials, including mGlurR5 agonists and inhibitors of kynurenic acid biosynthesis.

2.3 GABA:

Postmortem findings in schizophrenia brain of reduced GABA synthesis by inhibitory

ED

interneurons, as evidenced by decreased glutamtamic acid decarboxylase (GAD67), and by a

PT

compensatory increase in postsynaptic density of GABAA receptors containing the 2 subunit,

have led to the development of selective GABAA receptor agonists as a strategy to improve

AC
CE

working memory (Lewis et al., 2004). The rationale is complicated, however, by the recent
finding that the nonselective GABAA antagonist (inverse agonist), flumazenil, improved working
memory in healthy subjects and schizophrenia patients, whereas lorazepam, which is a
nonselective GABAA agonist, markedly impaired working memory (Menzies et al., 2007). The
adverse cognitive effects of benzodiazepines may reflect sedation mediated by GABAA receptors
containing 1 and 5 subunits.

2.3.1 GABAA Agonists:

In a four-week placebo-controlled add-on pilot trial in 15 schizophrenia patients, Lewis and
colleagues (Lewis et al., 2008) administered MK-0777, which is a selective partial agonist at

ACCEPTED MANUSCRIPT

GABAA receptors containing 2 and 3 subunits. Results are difficult to interpret, since the two

groups were not well-matched at baseline due to the small sample size, and the pre-specified

RI
P

primary outcome measure (total score on the Repeated Battery for the Assessment of
Neuropsychological Status) was negative. However, large effect sizes suggestive of benefit for

SC

attention and working memory on the AX Continuous Performance Task (CPT) and N-Back
Task were noted. In addition, EEG results were suggestive of increased gamma band power in

NU

the frontal area. However, a recent placebo-controlled add-on trial of MK-0777 in 60

MA

schizophrenia patients failed to find any cognitive benefit, including negative findings on the
CPT and N-Back tasks (Buchanan et al., 2010a).

ED

2.3.2 Conclusion:

The evidence linking GABAA receptor activation and working memory impairment in

PT

schizophrenia remain intriguing and worthy of future therapeutic development of higher potency
GABAA 2 agonists. Because MK-0777 is a partial agonist with only 10%-20% of full agonist

AC
CE

activity, it may not represent an adequate test of this hypothesis. However, results with
benzodiazepine receptor agonists and antagonists suggest that an exclusive focus on GABAA
agonists, rather than antagonists, may be premature.

2.4. Serotonin:
2.4.1 Agents acting at 5HT1A, 5HT2A & 5HT6 receptors:
There are multiple classes of serotonin (5HT) receptors in the brain and several have been
targeted by cognitive enhancing drugs (Terry et al., 2008). 5HT6 receptors have received the
most attention, based in part on their exclusive location in hippocampus and cortex and because
5HT6 antagonists release acetylcholine and glutamate, which could enhance memory and

ACCEPTED MANUSCRIPT

attention (Johnson et al., 2008). Studies of the 5HT6 antagonist, SB 743457, in animals have

been promising, as were early studies in Alzheimers disease (Upton et al., 2008). Other

RI
P

investigators have studied 5HT1A partial agonists in schizophrenia: in a pilot trial, tandospirone
produced improvements in memory, verbal learning, and executive functioning (Sumiyoshi et

SC

al., 2001), whereas a placebo-controlled trial of buspirone in 73 schizophrenia patients that

employed a cognitive battery of eight tests assessed at three time points found improvement in

NU

only one test of attention at three months only (Sumiyoshi et al., 2007). 5HT1A antagonists have

MA

also demonstrated cognitive enhancement in animal models and are in development for
schizophrenia (Schechter et al., 2002). In a placebo-controlled trial in 30 schizophrenia patients,
the 5HT2A (and alpha2 adrenergic) antagonist, mianserine, added to first generation

ED

antipsychotics significantly improved memory (Poyurovsky et al., 2003). However, since

PT

second generation antipsychotics are 5HT2A antagonists with high occupancy at therapeutic
doses, this mechanism would not be expected to enhance cognitive effects of these drugs.

AC
CE

2.4.2 Conclusions: Serotonergic receptors have been identified as promising targets for
cognition (Roth et al., 2004) but to-date, none has demonstrated compelling evidence for efficacy
in schizophrenia. Trials with 5HT6 antagonists are awaited, given early promise in animal
models and in Alzheimers disease.

2.5 Acetylcholine:
Studies in animals and humans have demonstrated an essential role for acetylcholine, acting at
muscarinic and nicotinic receptors, in the regulation of attention, memory, and sensory
processing (Furey et al., 2000; Gold, 2004; Hasselmo and Bower, 1993; Vitiello et al., 1997).
Unlike Alzheimers disease, in which cholinergic dysregulation is associated with degeneration

ACCEPTED MANUSCRIPT

of cholinergic neurons, cholinergic dysregulation in schizophrenia is thought to result from

alterations in muscarinic and nicotinic receptor expression and function (Breese et al., 2000;

RI
P

Crook et al., 2001; Dean et al., 2002; el-Mallakh et al., 1991; Freedman et al., 1995). Whereas
activity of choline acetyl transferase (ChAT), a marker for cholinergic activity, is normal in

SC

schizophrenia brain, levels of ChAT correlate with cognitive performance, suggesting that, in the
compromised schizophrenia brain, increasing cholinergic transmission may improve cognition

NU

(Powchik et al., 1998). The study of cholinergic transmission and of drugs acting via cholinergic

MA

mechanisms is complicated by high rates of cigarettes smoking and by treatment with

anticholinergic agents in schizophrenia patients (Goff et al., 1992; Minzenberg et al., 2004). In
addition, several second generation antipsychotic drugs enhance release of acetylcholine in

PT

ED

prefrontal cortex (Ichikawa et al., 2002).

AC
CE

2.5.1 Nicotinic acetylcholine receptors:

Expression of low-affinity 7 and high-affinity 4 2 nicotinic acetylcholine receptors is

prominent in areas of the brain associated with cognitive deficits in schizophrenia, including
hippocampus, cortex, striatum and thalamus, and is reduced in hippocampi of patients with
schizophrenia compared to controls (Breese et al., 2000; Freedman et al., 1995). The reduced
binding density of high-affinity 4 2 nicotinic receptors in hippocampi of schizophrenia patients
is impressive given that exposure to nicotine and haloperidol increased 4 2 nicotinic receptor
density in rats (Breese et al., 2000). The 7 neuronal nicotinic acetylcholine subunit gene
(CHRNA7) has been implicated as a candidate risk gene in schizophrenia based on linkage at
15q14; moreover, the prevalence of CHRNA7 functional promoter variants is increased in

ACCEPTED MANUSCRIPT

schizophrenia subjects and a functional promoter polymorphism in CHRNA7 was associated

RI
P

with an auditory sensory processing deficit in healthy subjects (Leonard et al., 2002).

2.5.1.1 Nicotine:

SC

Nicotine enhances many aspects of cognition in both healthy subjects and people with
schizophrenia, although tachyphylaxis may develop with repeated administration. In a placebo-

NU

controlled single-dose crossover trial of transdermal nicotine in 60 nonsmoking schizophrenia

MA

patients and controls, nicotine significantly improved attentional performance in both groups and
inhibited impulsive responses to a greater degree in schizophrenia subjects than in controls (Barr
et al., 2008). Transdermal nicotine administration also improved novelty detection in

ED

schizophrenia nonsmokers (Jubelt et al., 2008) and improved delayed recognition memory in

PT

schizophrenia smokers (Myers et al., 2004). In a test that maximally taxed working memory,
nicotine improved performance in schizophrenia smokers and worsened performance in healthy

AC
CE

controls; greater activation of a regional network and greater modulation of thalamocortical

functional connectivity by nicotine were also observed in schizophrenia patients compared to
controls (Jacobsen et al., 2004).

2.5.1.2 DMXB-A:
Considerable industry investment has been directed at the development of agents acting at 7 or
4 2 nicotine receptors, generally either as partial agonists or positive allosteric modulators in
order to minimize the likelihood of tachyphylaxis. A placebo-controlled cross-over add-on pilot
study in 12 schizophrenia nonsmokers of two doses of the 7 partial agonist, DMXB-A, each
administered as a loading dose and a second maintenance dose during a single day of cognitive

ACCEPTED MANUSCRIPT

assessments, found significant improvement in the composite cognitive score with the lower

DMXB-A dose (Olincy et al., 2006). Inhibition of the P50 auditory evoked potential was also

RI
P

significantly improved. In a follow-up placebo-controlled crossover add-on trial of the same

two doses of DMXB-A, the duration of exposure to DMXB-A was increased to 4 weeks in a

SC

sample of 31 schizophrenia patients (Freedman et al., 2008). Neither dose improved cognition
compared to placebo, whereas the higher dose improved negative symptoms. Another 7

NU

agonist, trepisetron, has also produced promising results in single dose trials, including

MA

normalization of the P50 auditory evoked potential (Koike et al., 2005), but cognitive effects of
trepisetron in an 8-week placebo-controlled trial in 40 schizophrenia patients did not

PT

2.5.2 Muscarinic Agonists

ED

significantly differ from placebo (Shiina et al., 2010).

Several lines of evidence have implicated muscarinic receptors in cognitive dysfunction in

AC
CE

schizophrenia (Friedman, 2004). Muscarinic receptor density is reduced in many brain regions
of medication-free schizophrenia patients compared to healthy controls (Raedler et al., 2003); of
the five subtypes of muscarinic receptor, evidence is strongest for a reduction in M1 receptors
which are known to play a role in memory (Friedman, 2004). Drug development has focused on
selective M1 agonists, thereby avoiding unwanted side effects resulting from the activation of M2
and M3 receptors in the gut, heart, genitourinary tract and exocrine glands which may complicate
therapy with cholinesterase inhibitors. In a placebo-controlled four-week add-on pilot study in
20 schizophrenia patients, the M1/M4 agonist, xanomeline, significantly improved measures of
working memory and delayed memory compared to placebo, although this finding must be
considered preliminary since it was not corrected for multiple comparisons (Shekhar et al.,

ACCEPTED MANUSCRIPT

2008). Other M1 agonists are currently in development, including N-desmethylclozapine,

although recent evidence suggests it may be an antagonist rather than a partial agonist at human

RI
P

cortical M1 receptors (Thomas et al., 2010).

SC

2.5.3 Cholinesterase Inhibitors:

NU

2.5.3.1 Rivastigmine & donapezil:

MA

Activation of muscarinic and nicotinic acetylcholine receptors is enhanced by cholinesterase

inhibitors. Whereas cholinesterase inhibitors have demonstrated modest benefit in Alzheimers
disease, the evidence for cognitive benefit in schizophrenia has been less compelling. Several

ED

open-label add-on trials of rivastigmine and donapezil reported improvements in cognitive

PT

performance, whereas a series of small placebo-controlled trials failed to demonstrate benefit

(Fagerlund et al., 2007; Freudenreich et al., 2005; Friedman et al., 2002; Tugal et al., 2004). In a

AC
CE

large add-on trial reported by Keefe and colleagues (Keefe et al., 2008), 245 schizophrenia
patients were randomly assigned to donepezil titrated up to 10 mg/d or placebo for twelve weeks.
Donepezil did not improve performance on any cognitive test compared to placebo and was
associated with worsening of negative symptoms. In the observed case analysis, placebo was
associated with a greater improvement on the cognitive composite score compared to donepezil
(effect size 0.45 vs. 0.26, p=0.04).

2.5.3.2 Galantamine:
Galantamine is a nonselective cholinesterase inhibitor at higher doses and a relatively selective
positive allosteric modulator at nicotinic 4 2 and 7 receptors at lower doses. Evidence of

ACCEPTED MANUSCRIPT

cognitive benefit with galantamine has been mixed. One of two small controlled add-on trials

reported evidence suggestive of benefit for memory and attention in schizophrenia (Lee et al.,

RI
P

2007; Schubert et al., 2006) . Buchanan and colleagues (Buchanan et al., 2008) randomly
assigned 86 schizophrenia patients to a 12 week placebo-controlled trial of galantamine titrated

SC

up to a dose of 24 mg/d. Galantamine did not improve the cognitive composite score compared
to placebo, but did improve digit symbol score (a test of attention and processing speed) and the

NU

California Verbal Learning Test (verbal memory) while worsening performance on the GDS

MA

Distractibility Test. In contrast, the manufacturer, Johnson and Johnson, conducted an 8 week
placebo-controlled add-on trial in 100 schizophrenia patients randomized to an extended release
formulation of galantamine at doses of 16 mg/d and 24 mg/d and did not find benefit on the Brief

ED

Assessment of Cognition in Schizophrenia (BACS) battery or on additional measures of attention

PT

and processing speed (Clinicaltrials.gov NCT00077727). In addition, a small placebo-controlled

trial in which galantamine was administered at a higher dose of 32 mg/d reported cognitive

AC
CE

worsening (Dyer et al., 2008).

2.5.4 Conclusion:

The evidence is strong that both muscarinic and nicotinic acetylcholine receptors may play a role
in cognitive impairment in schizophrenia and remain promising targets, particularly for attention
and memory. To-date, the M1/M4 agonist, xanomeline, has demonstrated the most impressive
cognitive benefit with repeated dosing. Tachyphylaxis with nicotine receptor agonists and the
high prevalence of cigarette smoking in schizophrenia patients complicate therapies targeting
nicotine receptors, although positive allosteric modulators may circumvent these problems.

ACCEPTED MANUSCRIPT

2.6 Miscellaneous:

2.6.1 Modafinil:

RI
P

Modafinil is a wakefulness-promoting agent with an uncertain mechanism of action. It has been

reported to increase activity of catecholamines, glutamate, serotonin, GABA, orexin and

SC

histamine, and to enhance cognitive functioning in several models (Minzenberg and Carter,
2008). Turner and colleagues (Turner et al., 2004) found improvements in short-term verbal

NU

memory and attentional set-shifting in a placebo-controlled single-dose cross-over trial of

MA

modafinil 100 mg in 20 schizophrenia patients. Three groups have found changes in brain
activation patterns following a single dose of modafinil in placebo-controlled studies in the
absence of improvement in cognitive performance (Hunter et al., 2006; Minzenberg et al., 2008;

ED

Spence et al., 2005). However, despite encouraging results from single-dose studies, several

PT

small clinical trials have failed to find cognitive benefit with modafinil. Placebo-controlled,
eight-week add-on trials of modafinil up to 200 mg/d in samples of 20 and 24 schizophrenia

AC
CE

patients failed to find benefit for cognition despite a reduction in fatigue or sedation (Pierre et
al., 2007; Sevy et al., 2005), as did a placebo-controlled eight-week trial of modafinil up to 300
mg/d in 35 clozapine treated patients (Freudenreich et al., 2009). In addition, a four-week trial in
which 60 schizophrenia patients were randomly assigned to placebo or to three doses of
armodafinil (the active metabolite of modafinil) also did not find cognitive enhancement but
negative symptoms were improved(Kane et al., 2010).

2.6.2 Pregnenolone:
Pregnenolone, an endogenous neurosteroid, is reported to modulate GABAA and NMDA
receptors, as well as hippocampal dopamine. It is also involved in neurodevelopment and may

ACCEPTED MANUSCRIPT

have neuroprotective properties. In an eight-week placebo controlled trial add-on trial

comparing two doses of pregnenlone and DHEA in 58 schizophrenia patients, low dose (30

RI
P

mg/d) pregnenolone improved measures of attention (Matching to Sample Visual Search) and
memory (Delayed Match to Sample) as well as psychotic symptoms, compared to placebo,

SC

whereas pregnenolone 200 mg/d had no effect (Ritsner et al., 2010). Because effects of three
treatment groups on five cognitive outcomes were analyzed without correction for multiple

NU

comparisons, these positive findings need be interpreted with caution. In addition, an 8-week

MA

placebo controlled add-on pilot trial of pregnenolone 500 mg/d in 18 patients with schizophrenia
(9 in each treatment group) improved negative symptoms (Marx et al., 2009). Pregnenolone and
placebo did not differ in effects on the MCCB composite score (mean T score change of 7.0 for

ED

both) whereas the investigators noted both an inverse correlation between cognitive function and

PT

baseline pregnenolone blood concentrations and a positive correlation between change in

AC
CE

pregnenolone concentrations and improvement in cognition. .

2.7 Neuroprotection, Neuroplasticity and Cognitive Remediation:

The relative lack of success with a wide range of candidate therapeutic agents has led to the view
that cognitive deficits may not result from dysregulation of a single neurotransmitter or class of
receptors, but rather may reflect a more fundamental abnormality of wiring resulting from
abnormal neurodevelopment or from a neurodegenerative process. In keeping with this model,
potential therapeutic agents include neuroprotective agents, including neurosteroids (e.g.,
pregnenolone (Ritsner et al., 2010; Wojtal et al., 2006) ), anti-oxidants (e.g., N-acetyl cysteine
(Berk et al., 2008)), omega 3 fatty acids (Palacios-Pelaez et al., 2010), anti-inflammatory agents
(e.g., aspirin & celecoxib (Laan et al., 2010; Muller et al., 2010) ), agents such as memantidine

ACCEPTED MANUSCRIPT

(Lieberman et al., 2009) and lamotrigine (Goff et al., 2007) that protect against excitotoxicity,

and neurotrophic factors and agents involved in neurogenesis (e.g. erythropoietin (Wustenberg et

RI
P

al., 2010) and davuletide (Javitt, 2010) ). Neuroprotective agents would be expected to require
an extended duration of treatment to prevent, halt, or reverse neurotoxicity. None has

SC

convincingly demonstrated cognitive benefits, although in a recent pilot study, omega 3 fatty
acids appeared to prevent high-risk individuals from progressing to schizophrenia when

MA

NU

administered for only 12 weeks (Amminger et al., 2010) .

2.7.1 Cognitive remediation:

Perhaps the best-supported therapeutic approach based on a neurodevelopmental model for

ED

cognitive deficits in schizophrenia is cognitive remediation. Although the mechanism remains

PT

speculative, cognitive remediation has demonstrated cognitive benefits in most studies as

demonstrated by a meta-analysis(McGurk et al., 2007), although at least one well-designed study

AC
CE

found that cognitive improvement failed to generalize beyond practice effects on tests
administered as part of the cognitive exercises (Dickinson et al., 2010). One approach to
cognitive remediation, based on principles of neuroplasticity, targets auditory discrimination; in
a randomized study in 55 schizophrenia subjects 50 hours of this method of cognitive
remediation produced broad improvement on most domains of the MCCB and significantly
elevated peripheral blood levels of the neurotrophin, BDNF, compared to an active control
condition (Adcock et al., 2009; Fisher et al., 2009; Vinogradov et al., 2009). Similarly, a twoyear intervention combining cognitive remediation and social skills training early in the course
of schizophrenia improved cognitive performance as measured by a composite cognitive score
(Eack et al., 2009); cognitive enhancement was associated with gray matter preservation in

ACCEPTED MANUSCRIPT

several brain regions as well as an increase in gray matter volume in the left amygdala (Eack et

al., 2010). However, it remains unclear what form of repetitive challenge is required to stimulate

RI
P

neuroplasticity; for example, daily aerobic exercise for a period of three months was also
associated with increased hippocampal volume and improved short-term memory in both

SC

schizophrenia patients and healthy subjects compared to a sedentary control group (Pajonk et al.,

NU

2010).

MA

2.7.2 Conclusion: Although the evidence supporting cognitive remediation has not yet achieved
the level necessary to merit inclusion in evidence-based treatment guidelines (Dixon et al.,
2010), this approach, combined with other psychosocial interventions, is promising. Several

ED

pharmacologic approaches are currently under study to facilitate neuroplasticity; these

PT

pharmacologic approaches might also be combined with cognitive remediation to explore a

AC
CE

possible synergist effect on cognition.

2.8 Summary:

Despite advances in genetics, imaging, and the post-mortem characterization of neurochemistry,

progress in the development of cognitive enhancing agents in schizophrenia has been relatively
disappointing. A wide range of pharmacological targets that are well-supported by basic
neuroscience have tended to produce promising findings in small pilot trials only to fail larger
replication trials. This pattern could reflect many possible factors, including early publication
bias towards positive studies lacking methodological and statistical rigor, whereas failure to
replicate could in part result from biological heterogeneity and the many obstacles associated
with clinical trials in psychiatry, including high placebo response rates, high attrition, poor

ACCEPTED MANUSCRIPT

adherence, and surreptitious substance abuse. It is also possible that current animal models used

in drug discovery do not adequately represent the complex neurodevelopmental abnormalities

RI
P

underlying cognitive impairment. While several approaches discussed in this review merit
further study, the generally disappointing results suggest that novel paradigms for target

SC

selection and clinical trial design also deserve consideration, possibly as exemplified by recent
work with cognitive remediation and agents that facilitate neuroprotection and neuroplasticity.

NU

Pharmacogenetic approaches in turn may improve our ability to detect treatment effects by

MA

reducing biological heterogeneity. Because cognitive impairment is a major cause of disability in

schizophrenia, the search for effective treatments must remain a high priority despite the

AC
CE

PT

ED

difficulty of this problem.

ACCEPTED MANUSCRIPT

References:

RI
P

Adcock, RA, Dale, C, Fisher, M, Aldebot, S, Genevsky, A, Simpson, GV, Nagarajan, S,

Vinogradov, S. When top-down meets bottom-up: auditory training enhances verbal memory in

SC

schizophrenia. Schizophr Bull 2009;35:1132-1141.

Amminger, GP, Schafer, MR, Papageorgiou, K, Klier, CM, Cotton, SM, Harrigan, SM,

NU

Mackinnon, A, McGorry, PD, Berger, GE. Long-chain omega-3 fatty acids for indicated
prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry

MA

2010;67:146-154.

Anand, A, Charney, DS, Oren, DA, Berman, RM, Hu, XS, Cappiello, A, Krystal, JH.

ED

Attentuation of the neuropsychiatric effects of ketamine with lamotrigine. Arch Gen Psychiatry
2000;57:270-276.

PT

Apud, JA, Mattay, V, Chen, J, Kolachana, BS, Callicott, JH, Rasetti, R, Alce, G, Iudicello, JE,

AC
CE

Akbar, N, Egan, MF, Goldberg, TE, Weinberger, DR. Tolcapone improves cognition and cortical
information processing in normal human subjects. Neuropsychopharmacology 2007;32:10111020.

Barch, DM, Carter, CS. Amphetamine improves cognitive function in medicated individuals
with schizophrenia and in healthy volunteers. Schizophr Res 2005;77:43-58.
Barch, DM, Mitropoulou, V, Harvey, PD, New, AS, Silverman, JM, Siever, LJ. Contextprocessing deficits in schizotypal personality disorder. J Abnorm Psychol 2004;113:556-568.
Barr, RS, Culhane, MA, Jubelt, LE, Mufti, RS, Dyer, MA, Weiss, AP, Deckersbach, T, Kelly,
JF, Freudenreich, O, Goff, DC, Evins, AE. The effects of transdermal nicotine on cognition in
nonsmokers with schizophrenia and nonpsychiatric controls. Neuropsychopharmacology
2008;33:480-490.

ACCEPTED MANUSCRIPT

Berk, M, Copolov, D, Dean, O, Lu, K, Jeavons, S, Schapkaitz, I, Anderson-Hunt, M, Judd, F,

Katz, F, Katz, P, Ording-Jespersen, S, Little, J, Conus, P, Cuenod, M, Do, KQ, Bush, AI. N-

placebo-controlled trial. Biol Psychiatry 2008;64:361-368.

RI
P

acetyl cysteine as a glutathione precursor for schizophrenia--a double-blind, randomized,

SC

Black, MD. Therapeutic potential of positive AMPA modulators and their relationship to AMPA
receptor subunits. A review of preclinical data. Psychopharmacology (Berl) 2005;179:154-163.

NU

Breese, CR, Lee, MJ, Adams, CE, Sullivan, B, Logel, J, Gillen, KM, Marks, MJ, Collins, AC,

MA

Leonard, S. Abnormal regulation of high affinity nicotinic receptors in subjects with

schizophrenia. Neuropsychopharmacology 2000;23:351-364.
Buchanan, RW, Barch, DM, Csernansky, J, Goff, DC, Gold, JM, jarskog, F, Javitt, DC, Keefe,

ED

RS, Lieberman, JA, McEvoy, JP, McMahon, FJ, Marder, SR. MK-0777 for the treatment of

PT

cognitive impairments in people with schizophrenia. Schiz Res 2010a;117:119.

Buchanan, RW, Conley, RR, Dickinson, D, Ball, MP, Feldman, S, Gold, JM, McMahon, RP.

AC
CE

Galantamine for the treatment of cognitive impairments in people with schizophrenia. Am J

Psychiatry 2008;165:82-89.

Buchanan, RW, Davis, M, Goff, D, Green, MF, Keefe, RS, Leon, AC, Nuechterlein, KH,
Laughren, T, Levin, R, Stover, E, Fenton, W, Marder, SR. A summary of the FDA-NIMHMATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia.
Schizophr Bull 2005;31:5-19.
Buchanan, RW, Javitt, DC, Marder, SR, Schooler, NR, Gold, JM, McMahon, RP, Heresco-Levy,
U, Carpenter, WT. The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST):
the efficacy of glutamatergic agents for negative symptoms and cognitive impairments. Am J
Psychiatry 2007;164:1593-1602.

ACCEPTED MANUSCRIPT

Buchanan, RW, Keefe, RS, Umbricht, D, Green, MF, Laughren, T, Marder, SR. The FDA-

NIMH-MATRICS Guidelines for Clinical Trial Design of Cognitive-Enhancing Drugs: What Do

RI
P

We Know 5 Years Later? Schizophr Bull 2010b.

Castner, SA, Goldman-Rakic, PS. Enhancement of working memory in aged monkeys by a

SC

sensitizing regimen of dopamine D1 receptor stimulation. J Neurosci 2004;24:1446-1450.

Castner, SA, Williams, GV, Goldman-Rakic, PS. Reversal of working memory deficits by short-

NU

term dopamine D1 receptor stimulation. Science 2000;287:2020-2022.

MA

Cornblatt, B, Obuchowski, M, Roberts, S, Pollack, S, Erlenmeyer-Kimling, L. Cognitive and

behavioral precursors of schizophrenia. Dev Psychopathol 1999;11:487-508.
Crook, JM, Tomaskovic-Crook, E, Copolov, DL, Dean, B. Low muscarinic receptor binding in

ED

prefrontal cortex from subjects with schizophrenia: a study of Brodmann's areas 8, 9, 10, and 46

PT

and the effects of neuroleptic drug treatment. Am J Psychiatry 2001;158:918-925.

Daniel, DG, Weinberger, DR, Jones, DW, Zigun, JR, Coppola, R, Handel, S, Bigelow, LB,

AC
CE

Goldberg, TE, Berman, KF, Kleinman, JE. The effect of amphetamine on regional cerebral blood
flow during cognitive activation in schizophrenia. J Neurosci 1991;11:1907-1917.
Davis, K, Kahn, R, Ko, G, Davidson, M. Dopamine in schizophrenia: A review and
reconceptualization. Am J Psychiatry 1991;148:1474-1486.
Davis, M, Ressler, K, Rothbaum, BO, Richardson, R. Effects of D-cycloserine on extinction:
translation from preclinical to clinical work. Biol Psychiatry 2006;60:369-375.
Dean, B, McLeod, M, Keriakous, D, McKenzie, J, Scarr, E. Decreased muscarinic1 receptors in
the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry 2002;7:10831091.

ACCEPTED MANUSCRIPT

Delawalla, Z, Barch, DM, Fisher Eastep, JL, Thomason, ES, Hanewinkel, MJ, Thompson, PA,

RI
P

individuals with schizophrenia. Schizophr Bull 2006;32:525-537.

Csernansky, JG. Factors mediating cognitive deficits and psychopathology among siblings of

Dickey, CC, McCarley, RW, Niznikiewicz, MA, Voglmaier, MM, Seidman, LJ, Kim, S,

SC

Shenton, ME. Clinical, cognitive, and social characteristics of a sample of neuroleptic-naive

persons with schizotypal personality disorder. Schizophr Res 2005;78:297-308.

NU

Dickinson, D, Tenhula, W, Morris, S, Brown, C, Peer, J, Spencer, K, Li, L, Gold, JM, Bellack,

Am J Psychiatry 2010;167:170-180.

MA

AS. A randomized, controlled trial of computer-assisted cognitive remediation for schizophrenia.

Dixon, LB, Dickerson, F, Bellack, AS, Bennett, M, Dickinson, D, Goldberg, RW, Lehman, A,

ED

Tenhula, WN, Calmes, C, Pasillas, RM, Peer, J, Kreyenbuhl, J. The 2009 schizophrenia PORT

PT

psychosocial treatment recommendations and summary statements. Schizophr Bull 2010;36:4870.

AC
CE

Dorph-Petersen, KA, Pierri, JN, Perel, JM, Sun, Z, Sampson, AR, Lewis, DA. The influence of
chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a
comparison of haloperidol and olanzapine in macaque monkeys. Neuropsychopharmacology
2005;30:1649-1661.

Dravid, SM, Burger, PB, Prakash, A, Geballe, MT, Yadav, R, Le, P, Vellano, K, Snyder, JP,
Traynelis, SF. Structural determinants of D-cycloserine efficacy at the NR1/NR2C NMDA
receptors. J Neurosci 2010;30:2741-2754.
Dyer, MA, Freudenreich, O, Culhane, MA, Pachas, GN, Deckersbach, T, Murphy, E, Goff, DC,
Evins, AE. High-dose galantamine augmentation inferior to placebo on attention, inhibitory

ACCEPTED MANUSCRIPT

control and working memory performance in nonsmokers with schizophrenia. Schizophr Res

2008;102:88-95.

RI
P

Eack, SM, Greenwald, DP, Hogarty, SS, Cooley, SJ, DiBarry, AL, Montrose, DM, Keshavan,
MS. Cognitive enhancement therapy for early-course schizophrenia: effects of a two-year

SC

randomized controlled trial. Psychiatr Serv 2009;60:1468-1476.

Eack, SM, Hogarty, GE, Cho, RY, Prasad, KM, Greenwald, DP, Hogarty, SS, Keshavan, MS.

NU

Neuroprotective Effects of Cognitive Enhancement Therapy Against Gray Matter Loss in Early

MA

Schizophrenia: Results From a 2-Year Randomized Controlled Trial. Arch Gen Psychiatry 2010.
Egan, MF, Goldberg, TE, Kolachana, BS, Callicott, JH, Mazzanti, CM, Straub, RE, Goldman, D,
Weinberger, DR. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk

ED

for schizophrenia. Proc Natl Acad Sci U S A 2001;98:6917-6922.

PT

el-Mallakh, RS, Kirch, DG, Shelton, R, Fan, KJ, Pezeshkpour, G, Kanhouwa, S, Wyatt, RJ,
Kleinman, JE. The nucleus basalis of Meynert, senile plaques, and intellectual impairment in

AC
CE

schizophrenia. J Neuropsychiatry Clin Neurosci 1991;3:383-386.

Fagerlund, B, Soholm, B, Fink-Jensen, A, Lublin, H, Glenthoj, BY. Effects of donepezil
adjunctive treatment to ziprasidone on cognitive deficits in schizophrenia: a double-blind,
placebo-controlled study. Clin Neuropharmacol 2007;30:3-12.
Fisher, M, Holland, C, Merzenich, MM, Vinogradov, S. Using neuroplasticity-based auditory
training to improve verbal memory in schizophrenia. Am J Psychiatry 2009;166:805-811.
Freedman, R, Hall, M, Adler, LE, Leonard, S. Evidence in postmortem brain tissue for decreased
numbers of hippocampal nicotinic receptors in schizophrenia. Biol Psychiatry 1995;38:22-33.
Freedman, R, Olincy, A, Buchanan, RW, Harris, JG, Gold, JM, Johnson, L, Allensworth, D,
Guzman-Bonilla, A, Clement, B, Ball, MP, Kutnick, J, Pender, V, Martin, LF, Stevens, KE,

ACCEPTED MANUSCRIPT

Wagner, BD, Zerbe, GO, Soti, F, Kem, WR. Initial phase 2 trial of a nicotinic agonist in

schizophrenia. Am J Psychiatry 2008;165:1040-1047.

RI
P

Freudenreich, O, Henderson, DC, Macklin, EA, Evins, AE, Fan, X, Cather, C, Walsh, JP, Goff,
DC. Modafinil for clozapine-treated schizophrenia patients: a double-blind, placebo-controlled

SC

pilot trial. J Clin Psychiatry 2009;70:1674-1680.

Freudenreich, O, Herz, L, Deckersbach, T, Evins, AE, Henderson, DC, Cather, C, Goff, DC.

NU

Added donepezil for stable schizophrenia: a double-blind, placebo-controlled trial.

MA

Psychopharmacology (Berl) 2005.

Friedman, JI. Cholinergic targets for cognitive enhancement in schizophrenia: focus on

cholinesterase inhibitors and muscarinic agonists. Psychopharmacology (Berl) 2004;174:45-53.

ED

Friedman, JI, Adler, DN, Howanitz, E, Harvey, PD, Brenner, G, Temporini, H, White, L,

PT

Parrella, M, Davis, KL. A double blind placebo controlled trial of donepezil adjunctive treatment
to risperidone for the cognitive impairment of schizophrenia. Biol Psychiatry 2002;51:349-357.

AC
CE

Furey, ML, Pietrini, P, Alexander, GE, Schapiro, MB, Horwitz, B. Cholinergic enhancement
improves performance on working memory by modulating the functional activity in distinct
brain regions: a positron emission tomography regional cerebral blood flow study in healthy
humans. Brain Res Bull 2000;51:213-218.
George, MS, Molnar, CE, Grenesko, EL, Anderson, B, Mu, Q, Johnson, K, Nahas, Z, Knable, M,
Fernandes, P, Juncos, J, Huang, X, Nichols, DE, Mailman, RB. A single 20 mg dose of
dihydrexidine (DAR-0100), a full dopamine D1 agonist, is safe and tolerated in patients with
schizophrenia. Schizophr Res 2007;93:42-50.

ACCEPTED MANUSCRIPT

Glahn, DC, Therman, S, Manninen, M, Huttunen, M, Kaprio, J, Lonnqvist, J, Cannon, TD.

Spatial working memory as an endophenotype for schizophrenia. Biol Psychiatry 2003;53:624-

RI
P

626.

Goff, D, Leahy, L, Berman, I, Posever, T, Herz, L, Leon, A, Johnson, S. A placebo-controlled

SC

pilot study of the ampakine, CX516, added to clozapine in schizophrenia. J Clin

Psychopharmacology 2001;21:484-487.

NU

Goff, D, Tsai, G, Levitt, J, Amico, E, Manoach, D, Schoenfeld, D, Hayden, D, McCarley, R,

MA

Coyle, J. A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in

patients with schizophrenia. Arch Gen Psych 1999;56:21-27.

Psychiatry 2005;13:352-359.

ED

Goff, DC. Pharmacologic implications of neurobiological models of schizophrenia. Harv Rev

PT

Goff, DC, Cather, C, Freudenreich, O, Henderson, DC, Evins, AE, Culhane, MA, Walsh, JP. A
placebo-controlled study of sildenafil effects on cognition in schizophrenia.

AC
CE

Psychopharmacology (Berl) 2009;202:411-417.

Goff, DC, Cather, C, Gottlieb, JD, Evins, AE, Walsh, J, Raeke, L, Otto, MW, Schoenfeld, D,
Green, MF. Once-weekly d-cycloserine effects on negative symptoms and cognition in
schizophrenia: An exploratory study. Schizophr Res 2008a;106:320-327.
Goff, DC, Coyle, JT. The emerging role of glutamate in the pathophysiology and treatment of
schizophrenia. Am J Psychiatry 2001;158:1367-1377.
Goff, DC, Henderson, DC, Amico, E. Cigarette smoking in schizophrenia: Relationship to
psychopathology and medication side effects. Amer J Psychiatry 1992;149:1189-1194.
Goff, DC, Herz, L, Posever, T, Shih, V, Tsai, G, Henderson, DC, Freudenreich, O, Evins, AE,
Yovel, I, Zhang, H, Schoenfeld, D. A six-month, placebo-controlled trial of D: -cycloserine co-

ACCEPTED MANUSCRIPT

administered with conventional antipsychotics in schizophrenia patients. Psychopharmacology

(Berl) 2005;179:144-150.

RI
P

Goff, DC, Keefe, R, Citrome, L, Davy, K, Krystal, JH, Large, C, Thompson, TR, Volavka, J,
Webster, EL. Lamotrigine as add-on therapy in schizophrenia: results of 2 placebo-controlled

SC

trials. J Clin Psychopharmacol 2007;27:582-589.

Goff, DC, Lamberti, JS, Leon, AC, Green, MF, Miller, AL, Patel, J, Manschreck, T,

NU

Freudenreich, O, Johnson, SA. A placebo-controlled add-on trial of the Ampakine, CX516, for

MA

cognitive deficits in schizophrenia. Neuropsychopharmacology 2008b;33:465-472.

Gold, JM, Goldberg, RW, McNary, SW, Dixon, LB, Lehman, AF. Cognitive correlates of job
tenure among patients with severe mental illness. Am J Psychiatry 2002;159:1395-1402.

ED

Gold, PE. Coordination of multiple memory systems. Neurobiol Learn Mem 2004;82:230-242.

PT

Goldberg, TE, Bigelow, LB, Weinberger, DR, Daniel, DG, Kleinman, JE. Cognitive and
behavioral effects of the coadministration of dextroamphetamine and haloperidol in

AC
CE

schizophrenia. Am J Psychiatry 1991;148:78-84.

Goldman-Rakic, PS, Castner, SA, Svensson, TH, Siever, LJ, Williams, GV. Targeting the
dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology
(Berl) 2004;174:3-16.

Green, MF, Kern, RS, Braff, DL, J., M. Neurocognitive deficits and functional outcome in
schizophrenia: are we measuring the "right stuff"? Schiz Bull 2000;26:119-136.
Green, MF, Kern, RS, Heaton, RK. Longitudinal studies of cognition and functional outcome in
schizophrenia: implications for MATRICS. Schizophr Res 2004;72:41-51.

ACCEPTED MANUSCRIPT

Hampson, RE, Rogers, G, Lynch, G, Deadwyler, S. Facilitative effects of the Ampakine CX516

on short term memory in rats: correlations with hippocampal neuronal activity. Journal of

RI
P

Neuroscience 1998;18:2748-2763.

Hasselmo, ME, Bower, JM. Acetylcholine and memory. Trends Neurosci 1993;16:218-222.

SC

Heaton, R, Gladsjo, JA, Palmer, BW, Kuck, J, Marcotte, TD, Jeste, DV. Stability and course of
neuropsychological deficits in schizophrenia. Arch Gen Psychiatry 2001;58:24-32.

NU

Heckers, S. Neuroimaging studies of the hippocampus in schizophrenia. Hippocampus

MA

2001:520-528.

Hunter, MD, Ganesan, V, Wilkinson, ID, Spence, SA. Impact of modafinil on prefrontal
executive function in schizophrenia. Am J Psychiatry 2006;163:2184-2186.

ED

Ichikawa, J, Dai, J, O'Laughlin, IA, Fowler, WL, Meltzer, HY. Atypical, but not typical,

PT

antipsychotic drugs increase cortical acetylcholine release without an effect in the nucleus
accumbens or striatum. Neuropsychopharmacology 2002;26:325-339.

AC
CE

Irani, F, Kalkstein, S, Moberg, EA, Moberg, PJ. Neuropsychological Performance in Older

Patients With Schizophrenia: A Meta-Analysis of Cross-sectional and Longitudinal Studies.
Schizophr Bull.

Jacobsen, LK, D'Souza, DC, Mencl, WE, Pugh, KR, Skudlarski, P, Krystal, JH. Nicotine effects
on brain function and functional connectivity in schizophrenia. Biol Psychiatry 2004;55:850-858.
Javitt, D, Zukin, S. Recent advances in the phencyclidine model of schizophrenia. Am J
Psychiatry 1991;148:1301-1308.
Javitt, DC. Effects of intranasal AL-108 (Davunetide) on neurocognition and functional outcome
in schizophrenia. Schiz Res 2010;119:118-119.

ACCEPTED MANUSCRIPT

Javitt, DC. Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry

2004;9:984-997, 979.

RI
P

Javitt, DC. Glycine transport inhibitors for the treatment of schizophrenia: symptom and disease
modification. Curr Opin Drug Discov Devel 2009;12:468-478.

SC

Jentsch, J, Roth, R. The neuropsychopharmacology of phencyclidine: From NMDA receptor

hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology

NU

1999;20:201-225.

MA

Johnson, CN, Ahmed, M, Miller, ND. 5-HT6 receptor antagonists: prospects for the treatment of
cognitive disorders including dementia. Curr Opin Drug Discov Devel 2008;11:642-654.
Jubelt, LE, Barr, RS, Goff, DC, Logvinenko, T, Weiss, AP, Evins, AE. Effects of transdermal

ED

nicotine on episodic memory in non-smokers with and without schizophrenia.

PT

Psychopharmacology (Berl) 2008;199:89-98.

Kane, JM, D'Souza, DC, Patkar, AA, Youakim, JM, Tiller, JM, Yang, R, Keefe, RS.

AC
CE

Armodafinil as adjunctive therapy in adults with cognitive deficits associated with

schizophrenia: a 4-week, double-blind, placebo-controlled study. J Clin Psychiatry 2010.
Kantrowitz, JT, Malhotra, D, Cornblatt, B, Silipo, G, Balla, A, Suckow, RF, D'Souza, DC,
Saksa, J, Woods, SW, Javitt, DC. High dose D-serine in the treatment of schizophrenia. Schiz
Res 2010;121:125-130.
Keefe, RS. Should cognitive impairment be included in the diagnostic criteria for schizophrenia?
World Psychiatry 2008;7:22-28.
Keefe, RS, Bilder, RM, Davis, SM, Harvey, PD, Palmer, BW, Gold, JM, Meltzer, HY, Green,
MF, Capuano, G, Stroup, TS, McEvoy, JP, Swartz, MS, Rosenheck, RA, Perkins, DO, Davis,

ACCEPTED MANUSCRIPT

CE, Hsiao, JK, Lieberman, JA. Neurocognitive effects of antipsychotic medications in patients

with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry 2007;64:633-647.

RI
P

Keefe, RS, Malhotra, AK, Meltzer, HY, Kane, JM, Buchanan, RW, Murthy, A, Sovel, M, Li, C,
Goldman, R. Efficacy and safety of donepezil in patients with schizophrenia or schizoaffective

SC

disorder: significant placebo/practice effects in a 12-week, randomized, double-blind, placebocontrolled trial. Neuropsychopharmacology 2008;33:1217-1228.

NU

Kegeles, LS, Abi-Dargham, A, Zea-Ponce, Y, Rodenhiser, J, Mann, JJ, Van Heertum, R, Cooper,

MA

TB, Carlsson, A, Laruelle, M. Modulation of amphetamine-induced striatal dopamine release by

ketamine in humans: Implications for schizophrenia. Biol Psychiatry 2000;48:627-640.
Koike, K, Hashimoto, K, Takai, N, Shimizu, E, Komatsu, N, Watanabe, H, Nakazato, M,

ED

Okamura, N, Stevens, KE, Freedman, R, Iyo, M. Tropisetron improves deficits in auditory P50

PT

suppression in schizophrenia. Schizophr Res 2005;76:67-72.

Konopaske, GT, Dorph-Petersen, KA, Pierri, JN, Wu, Q, Sampson, AR, Lewis, DA. Effect of

AC
CE

chronic exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque
monkeys. Neuropsychopharmacology 2007;32:1216-1223.
Krystal, JH, Abi-Saab, W, Perry, E, D'Souza, DC, Liu, N, Gueorguieva, R, McDougall, L,
Hunsberger, T, Belger, A, Levine, L, Breier, A. Preliminary evidence of attenuation of the
disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by
pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy
human subjects. Psychopharmacology (Berl) 2005;179:303-309.
Laan, W, Grobbee, DE, Selten, JP, Heijnen, CJ, Kahn, RS, Burger, H. Adjuvant aspirin therapy
reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind,
placebo-controlled trial. J Clin Psychiatry 2010;71:520-527.

ACCEPTED MANUSCRIPT

Lane, HY, Lin, CH, Huang, YJ, Liao, CH, Chang, YC, Tsai, GE. A randomized, double-blind,

RI
P

treatment for schizophrenia. Int J Neuropsychopharmacol 2009:1-10.

placebo-controlled comparison study of sarcosine ( N-methylglycine) and d-serine add-on

Laruelle, M, Abi-Dargham, A. Dopamine as the wind of the psychotic fire: new evidence from

SC

brain imaging studies. J Psychopharmacol 1999;13:358-371.

Lee, SW, Lee, JG, Lee, BJ, Kim, YH. A 12-week, double-blind, placebo-controlled trial of

NU

galantamine adjunctive treatment to conventional antipsychotics for the cognitive impairments in

MA

chronic schizophrenia. Int Clin Psychopharmacol 2007;22:63-68.

Leonard, S, Gault, J, Hopkins, J, Logel, J, Vianzon, R, Short, M, Drebing, C, Berger, R, Venn,
D, Sirota, P, Zerbe, G, Olincy, A, Ross, RG, Adler, LE, Freedman, R. Association of promoter

ED

variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit

PT

found in schizophrenia. Arch Gen Psychiatry 2002;59:1085-1096.

Lewis, DA, Cho, RY, Carter, CS, Eklund, K, Forster, S, Kelly, MA, Montrose, D. Subunit-

AC
CE

selective modulation of GABA type A receptor neurotransmission and cognition in

schizophrenia. Am J Psychiatry 2008;165:1585-1593.
Lewis, DA, Volk, DW, Hashimoto, T. Selective alterations in prefrontal cortical GABA
neurotransmission in schizophrenia: a novel target for the treatment of working memory
dysfunction. Psychopharmacology (Berl) 2004;174:143-150.
Lieberman, JA, Papadakis, K, Csernansky, J, Litman, R, Volavka, J, Jia, XD, Gage, A. A
randomized, placebo-controlled study of memantine as adjunctive treatment in patients with
schizophrenia. Neuropsychopharmacology 2009;34:1322-1329.

ACCEPTED MANUSCRIPT

Lisman, JE, Coyle, JT, Green, RW, Javitt, DC, Benes, FM, Heckers, S, Grace, AA. Circuit-based

framework for understanding neurotransmitter and risk gene interactions in schizophrenia.

RI
P

Trends Neurosci 2008;31:234-242.

Marx, CE, Keefe, RS, Buchanan, RW, Hamer, RM, Kilts, JD, Bradford, DW, Strauss, JL,

SC

Naylor, JC, Payne, VM, Lieberman, JA, Savitz, AJ, Leimone, LA, Dunn, L, Porcu, P, Morrow,
AL, Shampine, LJ. Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive

NU

and negative symptoms in schizophrenia. Neuropsychopharmacology 2009;34:1885-1903.

MA

Mattay, VS, Callicott, JH, Bertolino, A, Heaton, I, Frank, JA, Coppola, R, Berman, KF,
Goldberg, TE, Weinberger, DR. Effects of dextroamphetamine on cognitive performance and
cortical activation. Neuroimage 2000;12:268-275.

ED

Mattay, VS, Goldberg, TE, Fera, F, Hariri, AR, Tessitore, A, Egan, MF, Kolachana, B, Callicott,

PT

JH, Weinberger, DR. Catechol O-methyltransferase val158-met genotype and individual

variation in the brain response to amphetamine. Proc Natl Acad Sci U S A 2003;100:6186-6191.

AC
CE

McGurk, SR, Twamley, EW, Sitzer, DI, McHugo, GJ, Mueser, KT. A meta-analysis of cognitive
remediation in schizophrenia. Am J Psychiatry 2007;164:1791-1802.
Menzies, L, Ooi, C, Kamath, S, Suckling, J, McKenna, P, Fletcher, P, Bullmore, E, Stephenson,
C. Effects of gamma-aminobutyric acid-modulating drugs on working memory and brain
function in patients with schizophrenia. Arch Gen Psychiatry 2007;64:156-167.
Minzenberg, MJ, Carter, CS. Modafinil: a review of neurochemical actions and effects on
cognition. Neuropsychopharmacology 2008;33:1477-1502.
Minzenberg, MJ, Laird, AR, Thelen, S, Carter, CS, Glahn, DC. Meta-analysis of 41 functional
neuroimaging studies of executive function in schizophrenia. Arch Gen Psychiatry 2009;66:811822.

ACCEPTED MANUSCRIPT

Minzenberg, MJ, Poole, JH, Benton, C, Vinogradov, S. Association of anticholinergic load with

impairment of complex attention and memory in schizophrenia. Am J Psychiatry 2004;161:116-

RI
P

124.

Minzenberg, MJ, Watrous, AJ, Yoon, JH, Ursu, S, Carter, CS. Modafinil shifts human locus

SC

coeruleus to low-tonic, high-phasic activity during functional MRI. Science 2008;322:17001702.

NU

Moghaddam, B, Adams, B. Reversal of phencyclidine effects by a group II metabotropic

MA

glutamate receptor agonist. Science 1998;281:1349-1352.

Mu, Q, Johnson, K, Morgan, PS, Grenesko, EL, Molnar, CE, Anderson, B, Nahas, Z, Kozel, FA,
Kose, S, Knable, M, Fernandes, P, Nichols, DE, Mailman, RB, George, MS. A single 20 mg

ED

dose of the full D1 dopamine agonist dihydrexidine (DAR-0100) increases prefrontal perfusion

PT

in schizophrenia. Schizophr Res 2007;94:332-341.

Muller, N, Krause, D, Dehning, S, Musil, R, Schennach-Wolff, R, Obermeier, M, Moller, HJ,

AC
CE

Klauss, V, Schwarz, MJ, Riedel, M. Celecoxib treatment in an early stage of schizophrenia:

results of a randomized, double-blind, placebo-controlled trial of celecoxib augmentation of
amisulpride treatment. Schizophr Res 2010;121:118-124.
Myers, CS, Robles, O, Kakoyannis, AN, Sherr, JD, Avila, MT, Blaxton, TA, Thaker, GK.
Nicotine improves delayed recognition in schizophrenic patients. Psychopharmacology (Berl)
2004;174:334-340.
Niendam, TA, Bearden, CE, Rosso, IM, Sanchez, LE, Hadley, T, Nuechterlein, KH, Cannon,
TD. A prospective study of childhood neurocognitive functioning in schizophrenic patients and
their siblings. Am J Psychiatry 2003;160:2060-2062.

ACCEPTED MANUSCRIPT

Nong, Y, Huang, YQ, Ju, W, Kalia, LV, Ahmadian, G, Wang, YT, Salter, MW. Glycine binding

primes NMDA receptor internalization. Nature 2003;422:302-307.

RI
P

Nuechterlein, K, Green, MF. MATRICS Consensus Cognitive Battery (MCCB). Los Angeles:
MATRICS Assessments, Inc., 2006.

SC

Olincy, A, Harris, JG, Johnson, LL, Pender, V, Kongs, S, Allensworth, D, Ellis, J, Zerbe, GO,
Leonard, S, Stevens, KE, Stevens, JO, Martin, L, Adler, LE, Soti, F, Kem, WR, Freedman, R.

NU

Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry

MA

2006;63:630-638.

Pajonk, FG, Wobrock, T, Gruber, O, Scherk, H, Berner, D, Kaizl, I, Kierer, A, Muller, S, Oest,
M, Meyer, T, Backens, M, Schneider-Axmann, T, Thornton, AE, Honer, WG, Falkai, P.

ED

Hippocampal plasticity in response to exercise in schizophrenia. Arch Gen Psychiatry

PT

2010;67:133-143.

Palacios-Pelaez, R, Lukiw, WJ, Bazan, NG. Omega-3 essential Fatty acids modulate initiation

AC
CE

and progression of neurodegenerative disease. Mol Neurobiol 2010;41:367-374.

Parnas, AS, Weber, M, Richardson, R. Effects of multiple exposures to D-cycloserine on
extinction of conditioned fear in rats. Neurobiol Learn Mem 2005;83:224-231.
Patil, ST, Zhang, L, Martenyi, F, Lowe, SL, Jackson, KA, Andreev, BV, Avedisova, AS,
Bardenstein, LM, Gurovich, IY, Morozova, MA, Mosolov, SN, Neznanov, NG, Reznik, AM,
Smulevich, AB, Tochilov, VA, Johnson, BG, Monn, JA, Schoepp, DD. Activation of mGlu2/3
receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med
2007;13:1102-1107.

ACCEPTED MANUSCRIPT

Patterson, TL, Goldman, S, McKibbin, CL, Hughs, T, Jeste, DV. UCSD Performance-Based

Skills Assessment: development of a new measure of everyday functioning for severely mentally

RI
P

ill adults. Schizophr Bull 2001;27:235-245.

Pierre, JM, Peloian, JH, Wirshing, DA, Wirshing, WC, Marder, SR. A randomized, double-blind,

SC

placebo-controlled trial of modafinil for negative symptoms in schizophrenia. J Clin Psychiatry

2007;68:705-710.

NU

Pietrzak, RH, Snyder, PJ, Maruff, P. Use of an acute challenge with d-amphetamine to model

MA

cognitive improvement in chronic schizophrenia. Hum Psychopharmacol 2010;25:353-358.

Potter, MC, Elmer, GI, Bergeron, R, Albuquerque, EX, Guidetti, P, Wu, HQ, Schwarcz, R.
Reduction of endogenous kynurenic acid formation enhances extracellular glutamate,

ED

hippocampal plasticity, and cognitive behavior. Neuropsychopharmacology 2010;35:1734-1742.

PT

Powchik, P, Davidson, M, Haroutunian, V, Gabriel, SM, Purohit, DP, Perl, DP, Harvey, PD,
Davis, KL. Postmortem studies in schizophrenia. Schizophr Bull 1998;24:325-341.

AC
CE

Poyurovsky, M, Koren, D, Gonopolsky, I, Schneidman, M, Fuchs, C, Weizman, A, Weizman, R.

Effect of the 5-HT2 antagonist mianserin on cognitive dysfunction in chronic schizophrenia
patients: an add-on, double-blind placebo-controlled study. Eur Neuropsychopharmacol
2003;13:123-128.

Raedler, TJ, Knable, MB, Jones, DW, Urbina, RA, Gorey, JG, Lee, KS, Egan, MF, Coppola, R,
Weinberger, DR. In vivo determination of muscarinic acetylcholine receptor availability in
schizophrenia. Am J Psychiatry 2003;160:118-127.
Reichenberg, A, Harvey, PD. Neuropsychological impairments in schizophrenia: Integration of
performance-based and brain imaging findings. Psychol Bull 2007;133:833-858.

ACCEPTED MANUSCRIPT

Reneerkens, OA, Rutten, K, Steinbusch, HW, Blokland, A, Prickaerts, J. Selective

phosphodiesterase inhibitors: a promising target for cognition enhancement.

RI
P

Psychopharmacology (Berl) 2009;202:419-443.

Ritsner, MS, Gibel, A, Shleifer, T, Boguslavsky, I, Zayed, A, Maayan, R, Weizman, A, Lerner,

SC

V. Pregnenolone and dehydroepiandrosterone as an adjunctive treatment in schizophrenia and

schizoaffective disorder: an 8-week, double-blind, randomized, controlled, 2-center, parallel-

NU

group trial. J Clin Psychiatry 2010.

MA

Roth, BL, Hanizavareh, SM, Blum, AE. Serotonin receptors represent highly favorable
molecular targets for cognitive enhancement in schizophrenia and other disorders.
Psychopharmacology (Berl) 2004;174:17-24.

ED

Schechter, LE, Dawson, LA, Harder, JA. The potential utility of 5-HT1A receptor antagonists in

2002;8:139-145.

PT

the treatment of cognitive dysfunction associated with Alzheimer s disease. Curr Pharm Des

AC
CE

Schlumberger, C, Pietraszek, M, Gravius, A, Danysz, W. Effects of a positive allosteric

modulator of mGluR5 ADX47273 on conditioned avoidance response and PCP-induced
hyperlocomotion in the rat as models for schizophrenia. Pharmacol Biochem Behav 2009;95:2330.

Schubert, MH, Young, KA, Hicks, PB. Galantamine improves cognition in schizophrenic
patients stabilized on risperidone. Biol Psychiatry 2006;60:530-533.
Sevy, S, Rosenthal, MH, Alvir, J, Meyer, S, Visweswaraiah, H, Gunduz-Bruce, H, Schooler, NR.
Double-blind, placebo-controlled study of modafinil for fatigue and cognition in schizophrenia
patients treated with psychotropic medications. J Clin Psychiatry 2005;66:839-843.

ACCEPTED MANUSCRIPT

Shekhar, A, Potter, WZ, Lightfoot, J, Lienemann, J, Dube, S, Mallinckrodt, C, Bymaster, FP,

McKinzie, DL, Felder, CC. Selective muscarinic receptor agonist xanomeline as a novel

RI
P

treatment approach for schizophrenia. Am J Psychiatry 2008;165:1033-1039.

Shiina, A, Shirayama, Y, Niitsu, T, Hashimoto, T, Yoshida, T, Hasegawa, T, Haraguchi, T,

SC

Kanahara, N, Shiraishi, T, Fujisaki, M, Fukami, G, Nakazato, M, Iyo, M, Hashimoto, K. A

randomised, double-blind, placebo-controlled trial of tropisetron in patients with schizophrenia.

NU

Ann Gen Psychiatry 2010;9:27.

MA

Snitz, BE, Macdonald, AW, 3rd, Carter, CS. Cognitive deficits in unaffected first-degree
relatives of schizophrenia patients: a meta-analytic review of putative endophenotypes.
Schizophr Bull 2006;32:179-194.

ED

Sorensen, HJ, Mortensen, EL, Parnas, J, Mednick, SA. Premorbid neurocognitive functioning in

PT

schizophrenia spectrum disorder. Schizophr Bull 2006;32:578-583.

Spence, SA, Green, RD, Wilkinson, ID, Hunter, MD. Modafinil modulates anterior cingulate

AC
CE

function in chronic schizophrenia. Br J Psychiatry 2005;187:55-61.

Staubli, U, Rogers, G, Lynch, G. Facilitation of glutamate receptors enhances memory. Proc.
Natl. Acad. Sci. USA 1994;91:777-781.
Sumiyoshi, T, Matsui, M, Nohara, S, Yamashita, I, Kurachi, M, Sumiyoshi, C, Jayathilake, K,
Meltzer, HY. Enhancement of cognitive performance in schizophrenia by addition of
tandospirone to neuroleptic treatment. Am J Psychiatry 2001;158:1722-1725.
Sumiyoshi, T, Park, S, Jayathilake, K, Roy, A, Ertugrul, A, Meltzer, HY. Effect of buspirone, a
serotonin1A partial agonist, on cognitive function in schizophrenia: a randomized, double-blind,
placebo-controlled study. Schizophr Res 2007;95:158-168.

ACCEPTED MANUSCRIPT

Terry, AV, Jr., Buccafusco, JJ, Wilson, C. Cognitive dysfunction in neuropsychiatric disorders:

selected serotonin receptor subtypes as therapeutic targets. Behav Brain Res 2008;195:30-38.

RI
P

Thomas, DR, Dada, A, Jones, GA, Deisz, RA, Gigout, S, Langmead, CJ, Werry, TD, Hendry, N,
Hagan, JJ, Davies, CH, Watson, JM. N-desmethylclozapine (NDMC) is an antagonist at the

SC

human native muscarinic M(1) receptor. Neuropharmacology 2010;58:1206-1214.

Tsai, G, Lane, HY, Yang, P, Chong, MY, Lange, N. Glycine transporter I inhibitor, N-

NU

methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biol

MA

Psychiatry 2004;55:452-456.

Tugal, O, Yazici, KM, Anil Yagcioglu, AE, Gogus, A. A double-blind, placebo controlled,
cross-over trial of adjunctive donepezil for cognitive impairment in schizophrenia. Int J

ED

Neuropsychopharmacol 2004;7:117-123.

PT

Tuominen, HJ, Tiihonen, J, Wahlbeck, K. Glutamatergic drugs for schizophrenia: a systematic

review and meta-analysis. Schizophr Res 2005;72:225-234.

AC
CE

Turner, DC, Clark, L, Pomarol-Clotet, E, McKenna, P, Robbins, TW, Sahakian, BJ. Modafinil
improves cognition and attentional set shifting in patients with chronic schizophrenia.
Neuropsychopharmacology 2004;29:1363-1373.
Tuulio-Henriksson, A, Arajarvi, R, Partonen, T, Haukka, J, Varilo, T, Schreck, M, Cannon, T,
Lonnqvist, J. Familial loading associates with impairment in visual span among healthy siblings
of schizophrenia patients. Biol Psychiatry 2003;54:623-628.
Upton, N, Chuang, TT, Hunter, AJ, Virley, DJ. 5-HT6 receptor antagonists as novel cognitive
enhancing agents for Alzheimer's disease. Neurotherapeutics 2008;5:458-469.
Uslaner, JM, Parmentier-Batteur, S, Flick, RB, Surles, NO, Lam, JS, McNaughton, CH,
Jacobson, MA, Hutson, PH. Dose-dependent effect of CDPPB, the mGluR5 positive allosteric

ACCEPTED MANUSCRIPT

modulator, on recognition memory is associated with GluR1 and CREB phosphorylation in the

prefrontal cortex and hippocampus. Neuropharmacology 2009;57:531-538.

RI
P

Vinogradov, S, Fisher, M, Holland, C, Shelly, W, Wolkowitz, O, Mellon, SH. Is serum brainderived neurotrophic factor a biomarker for cognitive enhancement in schizophrenia? Biol

SC

Psychiatry 2009;66:549-553.

Vitiello, B, Martin, A, Hill, J, Mack, C, Molchan, S, Martinez, R, Murphy, DL, Sunderland, T.

NU

Cognitive and behavioral effects of cholinergic, dopaminergic, and serotonergic blockade in

MA

humans. Neuropsychopharmacology 1997;16:15-24.

Voglmaier, MM, Seidman, LJ, Niznikiewicz, MA, Dickey, CC, Shenton, ME, McCarley, RW.
Verbal and nonverbal neuropsychological test performance in subjects with schizotypal

ED

personality disorder. Am J Psychiatry 2000;157:787-793.

PT

Wojtal, K, Trojnar, MK, Czuczwar, SJ. Endogenous neuroprotective factors: neurosteroids.

Pharmacol Rep 2006;58:335-340.

AC
CE

Wustenberg, T, Begemann, M, Bartels, C, Gefeller, O, Stawicki, S, Hinze-Selch, D, Mohr, A,

Falkai, P, Aldenhoff, JB, Knauth, M, Nave, KA, Ehrenreich, H. Recombinant human
erythropoietin delays loss of gray matter in chronic schizophrenia. Mol Psychiatry 2010.

ACCEPTED MANUSCRIPT

Research Highlights

RI
P

SC

NU
MA

ED

PT

Cognitive deficits are a major cause of disability in schizophrenia

A wide range of approaches to cognitive enhancement have yielded largely disappointing
results
One possible explanation is the heterogeneity of mechanisms underlying cognitive
impairment
Promising results from cognitive remediation suggest a role for promotion of
neuroplasticity
Novel paradigms are required to tackle this problem

AC
CE